Abstract: Renal cell cancer (RCC) is a devastating cancer with a very low 5-year survival rate for patients who present with local or distant spread. RCC has stunning resistance to radiotherapy and chemotherapy, rampant epithelial-mesenchymal transition (EMT), as well as a hypoxic microenvironment ? all factors indicative of cancer stem cells (CSCs). Many lines of treatment have been trialed against RCC with positive results for receptor tyrosine kinase inhibitors, mTOR inhibitors, and more recently anti-PD1 therapy (nivolumab). However, although these drugs provide improvements in progression-free survival, most fail to improve overall survival. An exception to this is nivolumab, which targeted a new cell type, enhancing the immune system and leading to a paradigm shift in cancer treatment. COARE Biotechnology?s novel monoclonal antibody therapy CBT-15 is targeted to a specific cell type (CSCs) that may result in a similar paradigm shift. Doublecortin-like kinase 1 (DCLK1) is a prominent stem cell marker in gastrointestinal cancers and that is emerging in others. Our preliminary data demonstrates that specific extracellular DCLK1 isoforms are overexpressed in RCC stem-like cells and can be targeted to reverse drug-resistance, EMT, and oncogenic processes. With this knowledge, we developed an isoform-specific monoclonal antibody (CBT-15) to specifically target these CSCs in RCC. In vitro assays with this antibody demonstrate ADCC activity and in vivo studies using RCC xenografts demonstrate potent inhibition of tumorigenesis. Moreover, we have humanized CBT-15 and engineered an ADCC-enhanced version of the drug to increase potency (CBT-15AC). We propose further development and safety studies for CBT-15 to advance it to the market with the Fast-Track SBIR studies proposed here: Phase I Aim 1: Establish optimal delivery of CBT-15 and CBT-15AC DCLK1-targeted mABs in immunocompetent Renca xenografts and standard human RCC cell-line derived xenografts. Aim 2: Establish CBT-15 and CBT-15AC efficacy against tumorigenesis and metastasis in the clinically-relevant, orthotopic Renca model of RCC as a primary therapy and as an adjuvant to sunitinib or anti-PD1. Phase II Aim 3: Perform IND-enabling safety assessments for toxicity, pharmacokinetics, and tissue cross-reactivity of hCBT-15/CBT-15AC in murine and non-human primate models in preparation for human clinical trials. Desired Outcome: Phase I SBIR success will provide further proof-of-concept and be key to bringing investors on-board to support clinical trials and commercialization. Phase II SBIR success will provide the key results and data needed to pursue SBIR Phase IIB studies and engage the FDA for regulatory approval required to begin clinical trials in RCC patients. Clinical trial success will lead to ultimate commercialization. When CBT-15 reaches the market, COARE Holdings envisions a paradigm-shift in RCC therapy and survival.